Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells

Cretella, Daniele; Fumarola, Claudia; Bonelli, Mara; Alfieri, Roberta; Monica, Silvia La; Digiacomo, Graziana; Cavazzoni, Andrea; Galetti, Maricla; Generali, Daniele; Petronini, Pier Giorgio

doi:10.1038/s41598-019-49484-4

Cited by 69 publications

(67 citation statements)

References 39 publications

(53 reference statements)

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“…Paclitaxel has been shown to be useful in the chemotherapy of multiple cancers, including breast cancer, 26 it retards cell cycle progression and induces apoptosis to inhibit tumor cell growth. 27 In order to reveal the function of circ_0006528 in PTX-resistant breast cancer cells, loss-of-function assays were performed, and we found that its knockdown decreased the IC50 value of PTX as well as hindered cell proliferation, migration, invasion and autophagy, and induced cell apoptosis in breast cancer in vitro. Therefore, we hypothesized that circ_0006528 might exist in breast cancer as an oncogene, and its biological function might be related to PTX resistance.…”

Section: Discussionmentioning

confidence: 96%

<p>Circ_0006528 Contributes to Paclitaxel Resistance of Breast Cancer Cells by Regulating miR-1299/CDK8 Axis</p>

Liu

Zhang

et al. 2020

OTT

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Background: Circular RNAs (circRNAs) have been reported to be involved in regulating the development of breast cancer. Paclitaxel (PTX) can be used for the chemotherapy of breast cancer. The study aimed to explore the role and mechanism of circ_0006528 in PTXresistant breast cancer progression. Methods: The levels of circ_0006528, microRNA-1299 (miR-1299) and cyclin-dependent kinase 8 (CDK8) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RNase R treatment was used to confirm that the circ_0006528 was a circular RNA. PTX resistance and cell proliferation were determined by Cell counting kit-8 (CCK-8) assay. Cell apoptosis, migration and invasion were analyzed by flow cytometry and Transwell assays, respectively. The levels of all proteins were examined by Western blot. The interaction between circ_0006528 and miR-1299 or CDK8 was predicted by online database confirmed by dualluciferase reporter and RNA immunoprecipitation (RIP) assays. Xenograft mice model was constructed to reveal the role of circ_0006528 on tumor growth in vivo. Results: Circ_0006528 was significantly up-regulated and miR-1299 was down-regulated in PTX-resistant breast cancer tissues and cells compared with control groups. CDK8 protein expression was dramatically upregulated in PTX-resistant breast cancer tissues and cells as compared to control groups. Loss-of-function experiments revealed that circ_0006528 knockdown decreased IC50 value of PTX and restrained proliferation, migration, invasion and autophagy, whereas induced apoptosis of PTX-resistant breast cancer cells in vitro. The inhibitory effects of sh-circ_0006528 on the progression of PTX-resistant breast cancer cells were reversed by decreasing miR-1299 or increasing CDK8 expression. Furthermore, circ_0006528 could modulate CDK8 expression by sponging miR-1299. Circ_0006528 silencing impeded the growth of PTX-resistant tumors by regulating miR-1299/CDK8 axis in vivo. Conclusion: Circ_0006528 partially contributed to PTX resistance of breast cancer cells through up-regulating CDK8 expression by sponging miR-1299.

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Section: Discussionmentioning

confidence: 96%

<p>Circ_0006528 Contributes to Paclitaxel Resistance of Breast Cancer Cells by Regulating miR-1299/CDK8 Axis</p>

Liu

Zhang

et al. 2020

OTT

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“…Interestingly, palbociclib also seems to be able to inhibit GLUT1 mediated glucose uptake and metabolism in TNBC cells [87,88]. Moreover, combination of palbociclib with a chemotherapeutic agent currently used for the treatment of TNBC patients (paclitaxel) inhibited cell proliferation and increased cell death more efficiently than single treatments, associated with a more marked effect on glucose uptake and consumption and on GLUT1 protein levels [87]. Additionally, combination of palbociclib with a PI3K/mTOR inhibitor (BYL719) enhanced the antitumoral effect of these agents and the negative effect of each of these drugs on glucose uptake and consumption and on GLUT1 protein levels (Table 1) [88].…”

Section: Palbociclibmentioning

confidence: 98%

“…Palbociclib, an orally-available inhibitor of CDK4 and CDK6, represents the most widely studied compound among cell cycle inhibitors [86]. Interestingly, palbociclib also seems to be able to inhibit GLUT1 mediated glucose uptake and metabolism in TNBC cells [87,88]. Moreover, combination of palbociclib with a chemotherapeutic agent currently used for the treatment of TNBC patients (paclitaxel) inhibited cell proliferation and increased cell death more efficiently than single treatments, associated with a more marked effect on glucose uptake and consumption and on GLUT1 protein levels [87].…”

Section: Palbociclibmentioning

confidence: 99%

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

Barbosa

Martel

2020

Cancers

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Reprogramming of cellular energy metabolism is widely accepted to be a cancer hallmark. The deviant energetic metabolism of cancer cells-known as the Warburg effect-consists in much higher rates of glucose uptake and glycolytic oxidation coupled with the production of lactic acid, even in the presence of oxygen. Consequently, cancer cells have higher glucose needs and thus display a higher sensitivity to glucose deprivation-induced death than normal cells. So, inhibitors of glucose uptake are potential therapeutic targets in cancer. Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer death in women worldwide. Overexpression of facilitative glucose transporters (GLUT), mainly GLUT1, in breast cancer cells is firmly established, and the consequences of GLUT inhibition and/or knockout are under investigation. Herein we review the compounds, both of natural and synthetic origin, found to interfere with uptake of glucose by breast cancer cells, and the consequences of interference with that mechanism on breast cancer cell biology. We will also present data where the interaction with GLUT is exploited in order to increase the efficiency or selectivity of anticancer agents, in breast cancer cells.

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“…Paclitaxel inhibits palbociclib-mediated AKT induction and downregulates the RB/E2F/c-myc signaling pathway. The sequential combination of palbociclib/paclitaxel can enhance the inhibitory effects on glucose metabolism, and pretreatment with palbociclib can significantly improve the therapeutic effect of chemotherapy [172]. However, the simultaneous use of palbociclib and paclitaxel produces an antagonistic effect.…”

Section: The Combined Treatment With Cdk Inhibitors and Other Agentsmentioning

confidence: 99%

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

347

216

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Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

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Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells

Cited by 69 publications

References 39 publications

<p>Circ_0006528 Contributes to Paclitaxel Resistance of Breast Cancer Cells by Regulating miR-1299/CDK8 Axis</p>

<p>Circ_0006528 Contributes to Paclitaxel Resistance of Breast Cancer Cells by Regulating miR-1299/CDK8 Axis</p>

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

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